Ionizable cationic lipids

Abstract

Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent transfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.

We claim: 
     
       1. A lipid nanoparticle comprising a lipid compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, an optionally substituted, variably saturated or unsaturated C 1 -C 20  alkyl and an optionally substituted, variably saturated or unsaturated C 6 -C 20  acyl; 
         L 1  and L 2  are each independently optionally substituted polyunsaturated C 6 -C 20  alkenyl; 
         m and o are each independently zero, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty; and 
         n is one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty. 
       
     
     
       2. The lipid nanoparticle of  claim 1 , comprising one or more polynucleotides. 
     
     
       3. The lipid nanoparticle of  claim 2 , comprising encapsulated DNA or RNA. 
     
     
       4. The lipid nanoparticle of  claim 3 , wherein said RNA is mRNA. 
     
     
       5. The lipid nanoparticle of  claim 4 , wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR). 
     
     
       6. The lipid nanoparticle of  claim 1 , further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid. 
     
     
       7. The lipid nanoparticle of  claim 1 , wherein L 1  and L 2  are each an optionally substituted polyunsaturated C 18  alkenyl. 
     
     
       8. The lipid nanoparticle of  claim 2 , wherein said lipid compound is: 
       
         
           
           
               
               
           
         
       
     
     
       9. A lipid nanoparticle comprising a lipid compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are each independently selected from the group consisting of an optionally substituted, variably saturated or unsaturated C 6 -C 20  alkyl and an optionally substituted, variably saturated or unsaturated C 6 -C 20  acyl; 
         L 1  and L 2  are each independently optionally substituted polyunsaturated C 6 -C 20  alkenyl; and 
         m, n and o are each independently selected from the group consisting of zero, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty. 
       
     
     
       10. The lipid nanoparticle of  claim 9 , comprising one or more polynucleotides. 
     
     
       11. The lipid nanoparticle of  claim 10 , comprising encapsulated DNA or RNA. 
     
     
       12. The lipid nanoparticle of  claim 11 , wherein said RNA is mRNA. 
     
     
       13. The lipid nanoparticle of  claim 12 , wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine -4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR). 
     
     
       14. The lipid nanoparticle of  claim 9 , further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid. 
     
     
       15. The lipid nanoparticle of  claim 9 , wherein L 1  and L 2  are each an optionally substituted polyunsaturated C 18  alkenyl. 
     
     
       16. A lipid nanoparticle comprising:
 a lipid compound having the structure: 
 
       
         
           
           
               
               
           
         
          wherein
 R 1  and R 2  are each independently selected from the group consisting of an optionally substituted, variably saturated or unsaturated C 1 -C 20  alkyl and an optionally substituted, variably saturated or unsaturated C 6 -C 20  acyl; 
 L 1  and L 2  are each independently unsubstituted polyunsaturated C 18  alkenyl; and 
 x is selected from the group consisting of a C 5 -C 20  alkyl and a variably unsaturated C 1 -C 20  alkenyl; and 
 
         one or more polynucleotides. 
       
     
     
       17. The lipid nanoparticle of  claim 16 , comprising encapsulated DNA or RNA. 
     
     
       18. The lipid nanoparticle of  claim 17 , wherein said RNA is mRNA. 
     
     
       19. The lipid nanoparticle of  claim 18 , wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR). 
     
     
       20. The lipid nanoparticle of  claim 16 , further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid. 
     
     
       21. The lipid nanoparticle of  claim 16 , wherein x is a C 6 - 10  alkenyl or a C 6 - 10  alkyl. 
     
     
       22. The lipid nanoparticle of  claim 16 , wherein said lipid compound is: 
       
         
           
           
               
               
           
         
       
     
     
       23. The lipid nanoparticle of  claim 16 , wherein said lipid compoud is: